(−)-Δ9-trans-tetrahydrocannabinol is the active ingredient in marijuana. It is used therapeutically as an inhalant or an oral drug for stimulation of appetite among AIDS and cancer chemotherapy patients. Tetrahydrocannabinols (THCs) can be isolated from marijuana (a mixture of leaves and flowering heads of the plant Cannabis Sativa). Alternatively, THCs can be obtained by synthetic routes, e.g. as described in WO 02/096899. Enantiomerically pure THCs are required for formulation into drug products, but the purification of THCs, whether produced by isolation or synthesis, is challenging. The present inventors have sought to provide a process for providing enantiomerically pure (−)-Δ9-trans-tetrahydrocannabinol ((−)-Δ9-THC).
Chromatographic techniques have been used to separate (−)-Δ9-THC from other cannabinoid compounds. The identification of cannabis products in drug samples has been achieved using Supercritical Fluid Chromatography. Such methods are described by Bäckström et al (Science & Justice, 1997, 37(2), 91-97), Cole (“Analysis of Cannabis by Supercritical Fluid Chromatography with Ultraviolet Detection”, pages 145-148 in “Supercritical Fluid Methods and Protocols” ed. by Williams and Clifford), Veress (Journal of Chromatography A, 668 (1994), 285-291) and Later et al (Journal of Chromatographic Science, 1986, 24, 249-253). In these methods, very small samples (typically μg amounts) are analysed and the (−)-Δ9-THC is often destroyed during the detection step (e.g. by flame ionisation detection or by chemical ionisation mass spectrometry). These chromatographic methods achieve separation of (−)-Δ9-THC from other cannabinoid compounds, but are completely unsuitable for preparing sufficient quantities of enantiomerically pure (−)-Δ9-THC for incorporation into pharmaceutical products.
U.S. Pat. No. 6,403,126 addresses the problem of preparing (−)-Δ9-THC from marijuana. The patent describes the use of a supercritical fluid, such as carbon dioxide, as an extractant but not as an eluent in a chromatographic process. U.S. Pat. No. 6,403,126 does not demonstrate that (−)-Δ9-THC can be prepared using a supercritical fluid chromatographic process, and the only example uses a mobile phase of acetonitrile and water or methanol and water.
Levin et al (Journal of Chromatography A, 654 (1993), 53-64) have developed an analytical procedure for separating enantiomeric mixtures of cannabinoid compounds. The chromatographic method uses a Daicel Chiralpak® AD column, which is based on amylose tris(3,5-dimethylcarbamate) supported on macroporous silica gel. The mobile phase is n-hexane with ethanol or propanol. The enantioselective analysis determines the optical purity of samples but does not provide useful quantities of separated enantiomers.